Genome-wide interaction study of a proxy for stress-sensitivity and its prediction of major depressive disorder

Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Generation Scotland, Nese Direk, Erin C. Dunn, Jouke Jan Hottenga, Rick Jansen, Danielle Posthuma, Saira Saeed Mirza, Alexander Teumer, André G. Uitterlinden, Jian Yang, E. J.C. De Geus, Henning Tiemeier

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Individual response to stress is correlated with neuroticism and is an important predictor of both neuroticism and the onset of major depressive disorder (MDD). Identification of the genetics underpinning individual differences in response to negative events (stress-sensitivity) may improve our understanding of the molecular pathways involved, and its association with stress-related illnesses. We sought to generate a proxy for stress-sensitivity through modelling the interaction between SNP allele and MDD status on neuroticism score in order to identify genetic variants that contribute to the higher neuroticism seen in individuals with a lifetime diagnosis of depression compared to unaffected individuals. Meta-analysis of genome-wide interaction studies (GWIS) in UK Biobank (N = 23,092) and Generation Scotland: Scottish Family Health Study (N = 7,155) identified no genome-wide significance SNP interactions. However, gene-based tests identified a genome-wide significant gene, ZNF366, a negative regulator of glucocorticoid receptor function implicated in alcohol dependence (p = 1.48×10 -7 ; Bonferroni-corrected significance threshold p < 2.79×10 -6 ). Using summary statistics from the stress-sensitivity term of the GWIS, SNP heritability for stress-sensitivity was estimated at 5.0%. In models fitting polygenic risk scores of both MDD and neuroticism derived from independent GWAS, we show that polygenic risk scores derived from the UK Biobank stress-sensitivity GWIS significantly improved the prediction of MDD in Generation Scotland. This study may improve interpretation of larger genome-wide association studies of MDD and other stress-related illnesses, and the understanding of the etiological mechanisms underpinning stress-sensitivity.

Original languageEnglish
Article numbere0209160
JournalPLoS ONE
Issue number12
Publication statusPublished - Dec 2018

Bibliographical note

Funding Information:
Generation Scotland received core support from the Chief Scientist Office of the Scottish Government Health Directorates [CZD/16/6] and the Scottish Funding Council [HR03006]. Genotyping of the GS:SFHS samples was carried out by the Genetics Core Laboratory at the Wellcome Trust Clinical Research Facility, Edinburgh, Scotland and was funded by the Medical Research Council UK and the Wellcome Trust (Wellcome Trust Strategic Award "STratifying Resilience and Depression Longitudinally" (STRADL), Reference 104036/Z/14/Z). The Psychiatric Genomics Consortium has received major funding from the US National Institute of Mental Health and the US National Institute of Drug Abuse (U01 MH109528 and U01 MH1095320)The 1st author AAS is funded by University of Edinburgh ( and Medical Research Council for his PhD study at the University of Edinburgh Institute of Genetics and Molecular Medicine ( MA is supported by the Wellcome Trust Strategic Award STRADL (Reference 104036/Z/14/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Publisher Copyright:
© 2018 Arnau-Soler et al. This is an open access article distributed underthe terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


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